Cell adhesion inhibiting peptides exhibit potent anticancer activity and modulate intestinal microbiota. (December 2022)

• Record Type: Journal Article
• Authors: Chen, Yu-Fon; Yeh, Yao-Tsung; Su, Yu-Chu; Liao, Chorng-An; Huang, Cheng-Hsieh; Cheng, Ying-Jung; Jan, Jeng-Shiung
• Is Part Of: Materials & design. Volume 224(2022)
• Publication Date: 2022-12
• Subjects: Peptide drug -- E-cadherin -- Cell migration and adhesion -- Intestinal microbiota -- Akkermansia muciniphila (Akk) -- Prebiotic properties; Materials -- Periodicals; Engineering design -- Periodicals; Matériaux -- Périodiques; Conception technique -- Périodiques; Electronic journals; 620.11
• DOI: 10.1016/j.matdes.2022.111303
• Languages: English
• ISSNs: 0264-1275

Abstract

Graphical abstract: E-cadherin plays a critical role in cancer metastasis and needs Ca 2+ to package into intact and functional proteins. We report that the cationic, coil-sheet Lys5 BnCys5 peptide interacts with negatively charged molecules on cancer cell membranes by interfering E-cadherin packaging through various interactions. The peptide could efficiently induce caspase-3/PARP related apoptotic signaling and cause DNA condensation that leads to apoptosis. The peptide combined with low-dose cisplatin significantly inhibited tumor growth, prolonging the survival of tumor-bearing mice and suppressing lung metastasis. In intestinal microbiota analysis, Lys5 BnCys5 treatment increases the relative proportion of Akkermansia muciniphila . The peptide exhibits potent anticancer activity probably due to the synergistic effect of inhibiting cell migration/adhesion and modulating intestinal microbiota. Highlights: The peptide would interact with the cell membrane and affect normal E-cadherin expression through various interactions. The incorporation of benzyl group could greatly enhance the suppression of cancer cell migration and adhesion as well as apoptotic activity. The peptide effectively inhibits tumor growth and metastasis and exhibits prebiotic properties. The cell adhesion inhibiting peptide exhibits potent anticancer activity and modulates intestinal microbiota. Abstract: Membrane E-cadherin is one of the proteins whose expression affects cancer cell migration and adhesion. The design of peptide drugs that target such cancer cell-specific characteristics have received great attention in recent years and cysteine derivatives in particular have been shown to enhance anticancer effects. Herein, we set out to investigate the anticancer activity of a cell adhesion inhibiting peptide comprised of l -lysine (Lys) and Benzyl-l -cysteine (BnCys) and its influence on intestinal microbiota. The peptide inhibits cell migration and adhesion by interfering E-cadherin packaging, perturbing the integrity of cell membrane, and triggering caspase-3 and PARP related apoptotic pathways. It is highly possible that the cationic Lys segment would bind with the negatively charged cadherin molecules and the bulky BnCys segment would act as a spacing moiety to prevent the packing of E-cadherin. The peptide mixed with low-dose cisplatin effectively inhibits tumor growth and metastasis without incurring weight loss, prolonging the survival of tumor-bearing mice. The peptide treatment group increases the relative proportion of intestinal Akkermansia muciniphila (Akk), suggesting at prebiotic properties. These results paint a promising picture for designing cell migration/adhesion inhibiting peptides to target membrane E-cadherin for anticancer therapy.